A method of impinging jet high-throughput synthesis for spatial drug synthesis

Abstract

The application discloses a space medicine impact jet high-throughput synthesis method, and the whole process is divided into seven continuous procedures: three sets of microgravity correction models are calibrated and preloaded in orbit; two-stage gravity-free mixing is completed by adopting 180-degree coaxial opposed arrangement and herringbone channels, and the flow is dynamically adjusted according to a mixing time formula; the supersaturation deviation caused by microgravity is compensated by means of a nucleation rate formula; particles are cultivated by using a serpentine flow channel, and real-time closed-loop regulation and control of particle size is completed by using optical components; a buffer solution is introduced into the middle point of the flow channel to inhibit particle agglomeration; the product is sealed and collected, and the total yield is calculated in real time; after the pipeline is automatically flushed and the optical path is calibrated, the process is switched to low-power standby. The two-stage mixing method has high mixing efficiency, the particle size of the product is uniform, and the raw material utilization rate is higher than 90%; the process is equipped with space adaptive closed-loop regulation and control, and is matched with exhaust, particle stabilization and self-cleaning in-orbit procedures, and the whole process does not need manual operation, and is suitable for long-term high-throughput preparation of nanometer medicines on a spacecraft.

Description

Technical Field

[0001] This invention belongs to the field of space biomedicine and microfluidic chip technology, specifically relating to a high-throughput synthesis method using impact jets for space drug synthesis. Background Technology

[0002] The extreme environments of space microgravity, strong radiation, closed-loop circulation, and limited payload place stringent requirements on on-orbit drug delivery systems, including high uniformity, high feed utilization, high throughput, miniaturization, tolerance to extreme environments, and long-term stability.

[0003] Limitations of traditional nanomedicine preparation: Low mixing efficiency: It mainly relies on molecular diffusion and continuous laminar diffusion mixing, which is slow. Low raw material utilization rate; Particle size is not uniform; It relies on gravity assistance and has poor adaptability to microgravity environments in space;

[0004] The shortcomings of existing materials and technologies: lack of impact jet flow control formulas, high-throughput characteristic curves and on-orbit adaptive models for space environments, making it difficult to achieve accurate and controllable synthesis.

[0005] Therefore, there is an urgent need for an impact jet drug synthesis method that is suitable for microgravity environments, has high throughput, high uniformity, stable materials, and can be automated in orbit. Summary of the Invention

[0006] This invention addresses the problems of existing technologies by proposing a high-throughput impingement jet synthesis method for space drug synthesis. The first objective is to solve the problems of traditional nanomedicine synthesis relying on laminar diffusion mixing, which results in slow mixing speeds, gravity dependence, uneven mixing under microgravity, wide product particle size distribution, and low raw material utilization. The second objective is to address the lack of a quantitative control model adapted to microgravity in existing preparation processes, which only operate in an open-loop, constant-flow manner, failing to compensate for parameter drift caused by the space environment, leading to poor controllability and repeatability. The third objective is to address the lack of a complete set of processes adapted to space conditions, the tendency for microgravity to generate bubbles interfering with the optical path and jet, the easy aggregation of nanoparticles, and the absence of automatic cleaning, fault self-diagnosis, and on-orbit reuse processes. The fourth objective is to address the problem that existing technologies require significant manual intervention, making long-term unattended, fully automated, high-throughput synthesis in spacecraft impossible, and failing to meet the needs of on-orbit preparation, storage, and use of space drugs.

[0007] A high-throughput impingement jet synthesis method for space drug synthesis is characterized by being based on a space-based high-throughput impingement jet synthesis device. The core of this device is an aerospace-grade COC microfluidic chip, complemented by fluid delivery pipelines, a fluid injection interface, a sealed sample collection structure, and optical observation components. The COC microfluidic chip integrates a hairpin-type stabilizing input tube, a 180° coaxial counter-impinging mixing chamber, an interlaced herringbone-shaped secondary mixing channel, a serpentine particle growth channel with an optical detection window, a buffer midpoint dilution branch, and a full-channel cleaning pipeline. The method comprises the following steps:

[0008] Step 1: Preparation process: Power-on self-test of the entire machine in orbit, hardware calibration and pre-loading of the process model;

[0009] Step 2: Primary active mixing stage: precursor liquid delivery, 180° coaxial counter-current jet generation, and dynamic flow rate control by calling the mixing time formula;

[0010] Step 3: Synchronous nucleation stage: Primary active mixing stage: Secondary enhanced mixing through staggered herringbone channels, using the spatial nucleation rate formula to compensate for microgravity offset;

[0011] Step 4: Serpentine channel particle growth + in-situ real-time closed-loop monitoring of integrated optical components;

[0012] Step 5: Anti-agglomeration stabilization process: Online midpoint dilution of buffer solution to stabilize the nano-dispersion system;

[0013] Step 6: Collection and Statistics Process: The product is collected in a sealed manner on track, and the output is dynamically calculated in real time using the production formula;

[0014] Step 7: On-orbit reuse process: automatic cleaning of the flow channel, secondary calibration of the optical path, and finalization of the entire machine's standby operation.

[0015] Furthermore, the specific process of step 1 is as follows:

[0016] 1) When the spacecraft issues a start command, the entire synthesis device is powered on. The microcontroller synchronously drives the three-way flow pump, temperature / microgravity sensing module, and integrated optical detection component to start hardware self-test: verifying the airtightness of the COC microfluidic chip flow channel, the coaxiality of the optical path, the pump stroke accuracy, and the sensor signal path; if there is leakage, optical path obstruction, or pump control deviation, the process is automatically locked and the fault is reported.

[0017] 2) Hardware zero-point calibration and flow base logic lock: The three flow pumps complete the zero-point calibration and lock the basic ratio logic: the flow rates of the two precursor solutions are Q1=Q2 and the flow rates of the buffer diluent are Q3=2Q1; the total volume of the buffer solution in the sealed sample cell is set to 10 times the volume of the organic phase.

[0018] 3) Loading Space Quantization Control Formulas: The microcontroller reads real-time on-orbit environmental parameters (chamber temperature T, microgravity supersaturation offset ΔSspace, hybrid cavity feature size Dch, cavity morphology coefficient k), and pre-stores three sets of staged control formulas as the benchmark for the entire process:

[0019] 4) Raw material loading and flow channel pre-wetting: Connect the drug-loaded organic phase, aqueous antisolvent, and PBS buffer diluent to the three-way syringe respectively; the low-speed delivery fluid flows sequentially through the hairpin-shaped steady flow input tube, the pear-shaped mixing chamber, the staggered herringbone channel, and the serpentine optical detection flow channel to empty the air bubbles that are easy to accumulate under microgravity environment and eliminate jet pulsation and optical detection interference.

[0020] Furthermore, the specific steps of process 4) in step 1 are as follows:

[0021] ① Formula for mixing time of impingement jet (used during the counter-mixing stage): ;

[0022] Among them, t mix Mixing time (ms); k: cavity morphology coefficient; D ch : Characteristic dimensions of the mixing cavity (μm);

[0023] V jet : Impact jet velocity (m / s); Re: Impact Reynolds number;

[0024] ② Formula for the nucleation rate of nanoparticles (with spatial supersaturation correction);

[0025]

[0026] Where B: nucleation rate; k1: nucleation rate frequency factor; γ: surface tension; v m : Molar volume; kB: Boltzmann constant; T: Absolute temperature; Sᵣ: Ground supersaturation; ΔSspace: Space microgravity supersaturation offset;

[0027] ③ High-throughput production formula:

[0028] ;

[0029] in, C o : Precursor concentration (mg / ml); η: Raw material utilization rate (>90%); t: Synthesis time (min); Q1 and Q2 are the flow rates of the two precursor solutions, respectively.

[0030] Furthermore, the specific process of step 2 is as follows:

[0031] 1) The microcontroller drives the pump set to synchronously push organic phase and aqueous phase precursor liquid. The fluid enters the hairpin-shaped steady flow input pipe, and the flow pulsation is eliminated by the bending flow channel, so that the pressure and flow rate of the two fluids are kept consistent.

[0032] 2) The two fluids converge into the semi-circular upper chamber along the symmetrical inlet of the chip, forming a 180° concentric high-speed impact jet. The turbulence is generated by the fluid kinetic energy, breaking the traditional laminar molecular diffusion limitation.

[0033] 3) The sensing hardware collects the jet velocity Vjet and impact Reynolds number Re in real time. The microcontroller uses the microgravity correction mixing time formula to calculate the theoretical mixing time tmix in real time and automatically adjusts the precursor liquid flow rate in a closed loop.

[0034] 4) The counter-turbulent fluid flows downward into the conical lower chamber, completing the first stage of active impact mixing, and then enters the passive enhanced mixing channel.

[0035] Furthermore, the specific process of step 3 is as follows:

[0036] 1) The mixed fluid flows through the 40μm×40μm staggered herringbone channels that are repeatedly arranged along the central axis S in the conical lower cavity; the fluid continues to stratify, shear, and fold, further reducing the solute diffusion distance, and the system instantly reaches a highly supersaturated state.

[0037] 2) The microcontroller collects the real-time on-orbit temperature T, microgravity supersaturation offset ΔSspace, and ground reference supersaturation Sr, substitutes them into the space supersaturation correction nucleation rate formula to calculate the real-time nucleation rate B, and dynamically corrects the jet intensity.

[0038] 3) Under the synergistic effect of two-stage mixing, the solute bursts and nucleates simultaneously throughout the entire flow channel, controlling the uniformity of nanoparticles from the source of the process and ensuring that the product PDI < 0.15 in the high-throughput range.

[0039] Furthermore, the specific process of step 4 is as follows:

[0040] 1) After nucleation, the mixed fluid flows into the serpentine constant current output tube with an aspect ratio of >10:1. The long flow channel provides sufficient residence time, and the small crystal nuclei grow uniformly to the target particle size of 80~120nm. The COC chip in this solution is equipped with 2mm tempered glass, and the serpentine section is reserved with a dedicated coaxial optical detection window to adapt to vertical light path transmission.

[0041] 2) The integrated optical components are coaxially aligned with the detection window. The light source beam passes through the long-pass filter and the second set of functional filters in sequence to filter out short-wave scattering, spatial stray light, and solvent fluorescence interference, retaining only the characteristic scattering / transmission light signal of the nanoparticles. The signal receiving unit transmits a set of light intensity data back to the microcontroller every second.

[0042] 3) The microcontroller retrieves the pre-stored optical signal-particle size calibration curve and converts the light intensity into average particle size, dispersion index (PDI), and particle concentration in real time, forming a closed-loop control. This creates a fully automated closed-loop process of "counter-mixing - nucleation and growth - online optical detection - flow parameter self-correction." Ground-based devices only operate in an open-loop constant flow rate mode and lack real-time correction steps.

[0043] Furthermore, the specific process of step 5 is as follows:

[0044] 1) When the fluid flows to the midpoint of the buffer inlet at the end of the serpentine output tube, the microcontroller starts the third buffer pump and delivers the diluted buffer according to the preset ratio Q3=2×Q1.

[0045] 2) The buffer solution and the nanoparticle-containing stock solution are mixed uniformly online to rapidly reduce the concentration of organic solvent in the system, inhibit the aggregation and dissolution of nanoparticles, stabilize the dispersion system, and meet the requirements of long-term space storage.

[0046] 3) The optical components continuously collect the light signal of the diluted fluid. If the clustering characteristic scattering signal is detected, the microcontroller slightly increases the buffer flow rate to further reduce the solute concentration.

[0047] Furthermore, the specific process of step 6 is as follows:

[0048] 1) The diluted and stabilized nanodrug suspension is introduced into an aerospace-grade sealed pressure sample cell to complete the collection of the synthesized product in orbit. The sample cell can be directly used for astronaut drug delivery and long-term sealed storage.

[0049] 2) The entire synthesis process is continuously timed t. The microcontroller reads the precursor liquid concentration C0, two-channel flow rate, and measured raw material utilization rate η in real time. It continuously inputs the data into the high-throughput production calculation formula to dynamically calculate the cumulative total synthesis output Y. The output data is automatically stored in orbit and supports remote reading of output information from the ground.

[0050] 3) Automatic determination of synthesis endpoint: When the cumulative output Y reaches the preset target value, or the synthesis time reaches the set threshold, the microcontroller automatically shuts down the three flow pumps, and the optical components maintain a low-power standby monitoring state.

[0051] Furthermore, the specific process of step 7 is as follows:

[0052] 1) Switch the rinsing buffer pathway. Use high-flow PBS buffer to rinse the steady-flow input channel, pear-shaped mixing chamber, herringbone mixing channel, serpentine optical detection channel, and dilution tubing in sequence to remove residual drug nanoparticles from the tube walls and prevent long-term adsorption and blockage of the flow channels. The low adsorption properties of COC material greatly shorten the cleaning time.

[0053] 2) After rinsing, blank buffer solution is introduced again, and the optical components re-acquire the baseline light signal to eliminate the interference of trace residual impurities on the tube wall on the next round of detection.

[0054] 3) Turn off the light source, flow pump, and sensor module. The device enters a low-power on-orbit standby mode and waits for the next synthesis command. Advantages and effects of the present invention

[0055] 1. Full-process adaptation to microgravity extreme environment: The entire synthesis method, from premixing and hedging, nucleation correction, online quality control to dilution stabilization, is equipped with a space-corrected quantization model at all steps. It does not rely on gravity convection and perfectly solves the problem that the ground preparation process cannot operate stably in orbit.

[0056] 2. Fully automated closed-loop unmanned process: From self-inspection, synthesis, monitoring, collection to cleaning and reuse, a complete automated process is formed, which does not require manual operation by astronauts and is suitable for long-term unattended operation of spacecraft;

[0057] 3. Controllable product quality and high uniformity: Two-stage forced mixing + real-time optical feedback correction process stably produces 80~120nm narrow distribution nanomedicines with PDI < 0.15 and raw material utilization rate > 90%;

[0058] 4. High throughput, quantifiable and reusable: Synthesis throughput > 9 mL / min, real-time yield calculation throughout the process, supports continuous preparation of multiple samples; equipped with an automatic cleaning and calibration process, the device can be recycled multiple times, greatly improving the utilization efficiency of space pharmaceutical payloads;

[0059] 5. Strong anti-interference capability: Multiple process measures, including bubble pre-elimination, flow pulsation suppression, agglomeration dynamic control, and automatic fault lockout, avoid various process interferences caused by microgravity, radiation, and the closed environment of space, thereby improving the reliability of on-orbit synthesis. Attached Figure Description

[0060] Figure 1 This is an overall structural diagram of the space impact jet high-throughput synthesis device of the present invention;

[0061] Figure 2 This is a diagram showing the internal structure of the high-throughput spatial impact jet synthesis device of the present invention.

[0062] Figure 3 This is a top view of the COC microfluidic chip channel of the present invention;

[0063] Figure 4 This is a schematic diagram of the impact jet collision mixing principle of the present invention;

[0064] Figure 5 This is the particle size distribution characteristic curve of the drug of the present invention. Detailed Implementation Innovation of this invention

[0065] 1. Constructing a two-stage continuous mixing process using 180° coaxial counter-current and staggered herringbone patterns. Traditional nanomedicine preparation relies on laminar molecular diffusion mixing, which is slow and requires gravity convection to achieve solute homogenization. In microgravity environments, fluids lack natural stratification and convection, resulting in uneven mixing and asynchronous nucleation. Relying solely on passive groove shearing cannot achieve high-throughput, narrow-distribution product preparation. Conventional T-type / Y-type lateral confluence processes involve two fluid streams with a non-180° counter-current angle, which cannot completely cancel out the impulse and results in insufficient turbulence intensity. This invention employs two equal-flow-rate, coaxial, high-speed impacts of the fluids to create turbulence for primary mixing, combined with a hairpin channel to eliminate transport pulsation. The mixed fluid then undergoes stratification and shearing in a continuous staggered herringbone channel for secondary homogenization. The mixing time is <10ms, requiring no gravity assistance, and can simultaneously trigger global solute nucleation, stably controlling the product PDI below 0.15, achieving a synthesis throughput >9mL / min, and a raw material utilization rate exceeding 90%.

[0066] 2: A fully automated closed-loop control process linked by three-stage space correction quantification formulas. Traditional ground-based preparation only uses a fixed flow rate open-loop operation mode, lacking quantification correction logic adapted to microgravity; it cannot compensate for supersaturation shifts and mixing time drifts caused by microgravity; it lacks a real-time optical detection reverse correction process, resulting in poor repeatability of multiple batches of synthesized products and failing to meet the unmanned autonomous control requirements of spacecraft. This invention preloads three sets of microgravity-specific calculation formulas during the startup phase, presets a fixed flow rate ratio of Q1=Q2 and Q3=2Q1; during offset mixing, it calls the mixing time formula to adjust the flow rate in real time; during the nucleation stage, it uses the nucleation rate formula to compensate for microgravity supersaturation shifts; the production calculation formula is automatically calculated throughout the entire process; real-time optical acquisition of particle light signals is used to convert particle size and dispersion, and the fluid transport parameters are automatically corrected in reverse, forming a closed-loop self-control.

[0067] 3. A complete set of pretreatment, online particle stabilization, and self-cleaning processes adapted to microgravity environments. Conventional terrestrial preparation lacks space-specific anti-interference procedures: under microgravity, fluids lack gas-liquid interfaces, making it easy for air bubbles to accumulate in pipelines, interfering with jet stability and optical detection; nanoparticles in high-organic-phase systems are prone to agglomeration, lacking online stabilization processes; there are no automated cleaning and optical calibration processes, leading to batch cross-contamination due to drug residues, preventing continuous reuse in orbit; and there are no self-testing and fault handling procedures, making it impossible to automatically shut down in orbit in case of anomalies. This invention performs whole-machine self-testing calibration and full-channel pre-wetting to remove air bubbles before synthesis, avoiding in-orbit air bubble interference and equipment failure; after particle growth, buffer solution is quantitatively introduced at the midpoint of the channel for dilution, and the buffer solution flow rate is automatically increased upon detecting agglomeration signals to stabilize the dispersion system; after synthesis, the entire pipeline is automatically rinsed with PBS, the optical baseline is recalibrated, and the entire machine enters low-power standby mode, supporting multiple synthesis cycles.

[0068] 4. Seven-Segment Integrated Unmanned Fully Automated Continuous Synthesis Process. Traditional nanomedicine preparation processes are fragmented, requiring manual loading of raw materials, manual monitoring of particle status, manual collection of products, and manual cleaning of pipelines; they lack automatic yield statistics and automatic determination of synthesis endpoints, making them unsuitable for the stringent constraints of long-term unattended operation in satellite and manned spaceflight, and the low operational workload of astronauts. This invention designs a complete seven-step integrated process: self-test calibration pre-loading → 180° coaxial counter-flushing mixing → herringbone-shaped secondary shearing nucleation → serpentine flow channel growth + optical monitoring → midpoint buffer dilution → sealed collection and automatic yield determination shutdown → pipeline cleaning and optical calibration standby; it can receive remote commands from spacecraft to operate autonomously, and can be automatically started and stopped in case of faults or yield thresholds, requiring no manual operation throughout the entire process.

[0069] 5. Multi-parameter quantitative coupling synergistic preparation process. Traditional diffusion mixing processes suffer from low throughput and high raw material loss; the flow ratio lacks fixed quantitative constraints, making it impossible to simultaneously balance the three indicators of synthesis throughput, raw material utilization, and particle uniformity, which is insufficient to meet the needs of large-scale preparation of multiple samples in space. This invention limits the flow rates of the two precursor solutions to equal values, the buffer solution flow rate to twice that of the precursor solution, and the volume of the buffer solution in the sealed sample cell to 10 times that of the organic phase; relying on a fixed quantitative ratio to coordinate two-stage mixing and online dilution processes, it simultaneously achieves three core indicators: high throughput, high raw material utilization, and narrow particle size distribution (80~120nm). Explanation of control logic and formulas, and other related details:

[0070] 1. High-flux control logic for impingement jet

[0071] The control unit is a single-chip microcomputer closed-loop control of three flow pumps; the flow rates of two precursor solutions are Q1=Q2; the flow rate of the buffer solution is Q3=2×Q1; the volume of the sample cell buffer solution is 10 times the volume of the organic phase.

[0072] 2. Space Environment Control Formula

[0073] (1) Formula for mixing time of impingement jet (microgravity correction)

[0074] ;

[0075] Among them, t mix Mixing time (ms); k: cavity morphology coefficient; D ch : Characteristic dimensions of the mixing cavity (μm);

[0076] V jet : Impact jet velocity (m / s); Re: Impact Reynolds number;

[0077] (2) Formula for nucleation rate of nanoparticles (with spatial supersaturation correction)

[0078] ;

[0079] Where B: nucleation rate; k1: nucleation rate frequency factor; γ: surface tension; vm: molar volume; kB: Boltzmann constant; T: absolute temperature; S r : Ground supersaturation; ΔSspace: Space microgravity supersaturation offset.

[0080]

[0081] Y Synthesis time (min); Q1 and Q2 are the flow rates of the two precursor solutions, respectively.

[0082] 3. Spatial Composite Characteristic Curve

[0083] 1) Impact flow rate-particle size curve: flow rate 0.1–800 μl / min, particle size first decreases and then tends to stabilize as flow rate increases; in the high-throughput range (>9 ml / min), particle size is 80–120 nm, PDI < 0.15.

[0084] 2) Precursor concentration-homogeneity (PDI) curve: concentration 5–20 mg / ml, PDI stable 0.08–0.18, spatial drift <3%.

[0085] 3) Mixing time-supersaturation curve: The mixing time of the impingement jet is <1ms, the supersaturation reaches its peak rapidly, and the nucleation synchronization is significantly improved.

[0086] Based on the above principles, this invention designs a high-throughput impingement jet synthesis method for space drug synthesis. The method is characterized by being based on a space-based high-throughput impingement jet synthesis device. The core of this device is an aerospace-grade COC microfluidic chip, along with fluid delivery pipelines, a fluid injection interface, a sealed sample collection structure, and optical observation components. The COC microfluidic chip integrates a hairpin-type stabilizing input tube, a 180° coaxial counter-impinging mixing chamber, an interlaced herringbone-shaped secondary mixing channel, a serpentine particle growth channel with an optical detection window, a buffer midpoint dilution branch, and a full-channel cleaning pipeline. The method includes the following steps:

[0087] Step 1: Preparation process: Power-on self-test of the entire machine in orbit, hardware calibration and pre-loading of the process model;

[0088] Step 2: Primary active mixing stage: precursor liquid delivery, 180° coaxial counter-current jet generation, and dynamic flow rate control by calling the mixing time formula;

[0089] Step 3: Synchronous nucleation stage: Primary active mixing stage: Secondary enhanced mixing through staggered herringbone channels, using the spatial nucleation rate formula to compensate for microgravity offset;

[0090] Step 4: Serpentine channel particle growth + in-situ real-time closed-loop monitoring of integrated optical components;

[0091] Step 5: Anti-agglomeration stabilization process: Online midpoint dilution of buffer solution to stabilize the nano-dispersion system;

[0092] Step 6: Collection and Statistics Process: The product is collected in a sealed manner on track, and the output is dynamically calculated in real time using the production formula;

[0093] Step 7: On-orbit reuse process: automatic cleaning of the flow channel, secondary calibration of the optical path, and finalization of the entire machine's standby operation.

[0094] Supplementary Note 1: Figure 1 Comparative interpretation

[0095] Figure 1 This is a structural diagram of the high-throughput spatial impact jet synthesis device of the present invention. The entire flow channel integrates a three-way fluid input and a single-way finished product output structure. Two precursor liquid pipelines, Inlet 1 and Inlet 2, are set on the left side, symmetrically converging into the central 180° coaxial counter-current mixing chamber (the two pipelines will eventually converge to the two ends of the same diameter of the central circular chamber, and are injected into the chamber from the left and right ends along the same straight line. This step is the 180°. The front delivery sections of Inlet 1 and Inlet 2 follow a diagonal parallel line to eliminate pump flow pulsation, and are not the final angle of injection into the mixing chamber). Inlet 3 is an independent PBS buffer dilution branch. Inside the flow channel, the coaxial counter-current mixing chamber, the staggered herringbone secondary mixing channel, and the serpentine particle growth channel are connected in series. In this process, inlet liquids 1 and 2 undergo primary fluid mixing in the counter-fluid chamber, followed by secondary fine homogenization and mixing through an interlaced herringbone channel. The mixture then enters a serpentine flow channel for isothermal growth of nanocrystal nuclei. An optical detection window is reserved in the serpentine flow channel section for online monitoring of particle size distribution. Inlet liquid 3, a buffer solution, only merges into the main channel downstream of the serpentine flow channel and does not participate in the initial two-stage mixing process. It is used solely for online dilution of the organic solvent to prevent particle agglomeration under microgravity conditions in space. The final prepared drug solution is discharged through the end outlet to a sealed collection device, forming a continuous nanomedicine preparation process.

[0096] Supplementary Note 2: Figure 2 Comparative interpretation

[0097] Figure 2 This is a structural diagram of the internal structure of the high-throughput synthesis device for space impact jets of the present invention. Figure 1The on-orbit carrier packaging assembly of the microfluidic chip consists of three parts: a cyan-blue upper flip-top pressure plate, a purple lower base, and an embedded light green COC microfluidic chip. The integrated side hinge structure enables tool-free flip-top opening and closing, meeting the needs of rapid chip replacement within the confined space of the spacecraft. The upper flip-top features four sets of symmetrical clamping screws, working in conjunction with a ring seal to evenly press the chip at four points, ensuring no organic solvent leakage under high pressure and preventing microchannel deformation under pressure, thus guaranteeing the dimensional accuracy of the counter-jet and herringbone groove design. The base features a chip-proof positioning groove to ensure unique alignment of the flow channel, and both ends are pre-installed with quick-connect external connectors for connecting to external infusion lines and rear-end collection devices. The bottom of the base has a perforated, light-transmitting design for the serpentine flow channel area, compatible with external optical detection paths, enabling real-time closed-loop particle size control and adapting to continuous fabrication operations in a closed on-orbit environment.

[0098] Supplementary Note 3: Figure 3 Comparative Interpretation

[0099] Figure 3 This is a top view of the COC microfluidic chip channel of the present invention. Figure 2 The fixture's planar structure is shown. On the left is a slot-type fluid input docking interface for connecting a high-precision injection pump to deliver three streams of working fluid. The four concentric annular sealing and locking structures in the center are arranged symmetrically in a quadrilateral shape, corresponding one-to-one with the fixture's clamping points, relying on bolts and fluororubber sealing rings to hold the sealing chip interlayer. The light green area in the center is... Figure 1 The complete flow channel body sequentially arranges a coaxial counter-flushing mixing chamber, an interlaced herringbone-shaped secondary mixing channel, and a serpentine particle growth channel, continuing the two-stage mixing process of "primary counter-flushing + secondary groove shearing." The third buffer solution still merges into the main channel in the serpentine section. On the right is a bent fluid output adapter base. The bent structure adapts to the internal wiring of the equipment, and at the same time, the outlet flow rate is buffered by a gradually changing pipeline to prevent the formed nanoparticles from being sheared and broken by the high-speed fluid. Finally, the finished drug solution is smoothly discharged to the aerospace-grade sealed pressure-bearing collection device.

[0100] Supplementary Note 4: Figure 4 Comparative interpretation

[0101] Figure 4This is a schematic diagram illustrating the impact jet collision mixing principle of this invention; it represents the core innovative structure that distinguishes this invention from existing technologies. Jet source A and jet source B correspond to the two precursor liquid pipelines, inlet 1 and inlet 2, respectively. The two channels are arranged in a 180° coaxial straight line facing each other (in the attached diagram, jet source A and jet source B ultimately connect to the two ends of a diameter of a circular mixing chamber, and are injected into the center of the chamber at a 180° angle along a coaxial straight line, achieving frontal jet collision at the center). The fluids are ejected into the collision area at equal flow rates and pressures. The two jets collide head-on at the center point, their momentum canceling each other out and forming violent vortices, backflows, and shear turbulence. The fluids are instantly stretched and torn apart, significantly shortening the molecular diffusion distance and achieving millisecond-level first-stage coarse mixing. This method relies on the fluid's own kinetic energy for forced mixing, eliminating the need for gravity convection and preventing the mixing unevenness problem caused by gravity stratification. After the collision, the mixed fluid flows into the right-side gradually expanding pressure-stabilizing straight pipe. The interwoven streamlines inside the pipe indicate that the fluid has completed the initial mixing. The straight pipe directly connects to the rear-end staggered herringbone-shaped secondary mixing channel, forming a complete two-stage mixing process link. Compared with the traditional 90° T-shaped lateral convergence structure, this coaxial collision structure has higher mixing efficiency and stronger uniformity, which can ensure the synchronous precipitation of nanocrystal nuclei and improve the dispersion stability of the finished drug.

[0102] Supplementary Note 5: Figure 5 Comparative interpretation

[0103] Figure 5 This is the particle size distribution characteristic curve of the drug of this invention. The horizontal axis represents the hydrodynamic particle size, and the vertical axis represents the proportion of light intensity in the particles. With the 180° coaxial counter-current jet, the Reynolds number Re increases from 10 to 640, and the average particle size of the nanoparticles continuously decreases from about 500 nm to 100 nm. The peak width of the particle size distribution is significantly narrowed, and the polydispersity index (PDI) decreases. When Re≥400, the particles are stably distributed in the target range of 80–120 nm without large particle size agglomerates. This verifies that the two-stage mixing scheme of the impact jet of this invention can achieve the synthesis of highly uniform and high-throughput drug nanoparticles under microgravity environment, providing experimental data support for the on-orbit flow closed-loop control process.

[0104] Furthermore, the specific process of step 1 is as follows:

[0105] 1) When the spacecraft issues a start command, the entire synthesis device is powered on. The microcontroller synchronously drives the three-way flow pump, temperature / microgravity sensing module, and integrated optical detection component to start hardware self-test: verifying the airtightness of the COC microfluidic chip flow channel, the coaxiality of the optical path, the pump stroke accuracy, and the sensor signal path; if there is leakage, optical path obstruction, or pump control deviation, the process is automatically locked and the fault is reported.

[0106] 2) Hardware zero-point calibration and flow base logic lock: The three flow pumps complete the zero-point calibration and lock the basic ratio logic: the flow rates of the two precursor solutions are Q1=Q2 and the flow rates of the buffer diluent are Q3=2Q1; the total volume of the buffer solution in the sealed sample cell is set to 10 times the volume of the organic phase.

[0107] 3) Loading Space Quantization Control Formulas: The microcontroller reads real-time on-orbit environmental parameters (chamber temperature T, microgravity supersaturation offset ΔSspace, hybrid cavity feature size Dch, cavity morphology coefficient k), and pre-stores three sets of staged control formulas as the benchmark for the entire process:

[0108] 4) Raw material loading and flow channel pre-wetting: Connect the drug-loaded organic phase, aqueous antisolvent, and PBS buffer diluent to the three-way syringe respectively; the low-speed delivery fluid flows sequentially through the hairpin-shaped steady flow input tube, the pear-shaped mixing chamber, the staggered herringbone channel, and the serpentine optical detection flow channel to empty the air bubbles that are easy to accumulate under microgravity environment and eliminate jet pulsation and optical detection interference.

[0109] Furthermore, the specific steps of process 4) in step 1 are as follows:

[0110] ① Formula for mixing time of impingement jet (used during the counter-mixing stage): ;

[0111] Among them, t mix Mixing time (ms); k: cavity morphology coefficient; D ch : Characteristic dimensions of the mixing chamber (μm);

[0112] V jet : Impact jet velocity (m / s); Re: Impact Reynolds number;

[0113] ② Formula for the nucleation rate of nanoparticles (with spatial supersaturation correction);

[0114]

[0115] Where B: nucleation rate; k1: nucleation rate frequency factor; γ: surface tension; v m : Molar volume; kB: Boltzmann constant; T: Absolute temperature; Sᵣ: Ground supersaturation; ΔSspace: Space microgravity supersaturation offset;

[0116] ③ High-throughput production formula:

[0117] ;

[0118] Where Y: total yield (mg); C o: Precursor concentration (mg / ml); η: Raw material utilization rate (>90%); t: Synthesis time (min); Q1 and Q2 are the flow rates of the two precursor solutions, respectively.

[0119] Supplementary Note 6

[0120] The purpose of step 1 above is pre-operation preparation, similar to a "line-up" check in a workshop. It addresses the issue that existing technologies operating in space cannot be repaired promptly should a malfunction occur. This application is like giving the machine a "physical examination," checking all components (chips, pumps, sensors) for damage, leaks, and blockages during startup. If a problem is found, it immediately stops and reports to the ground. Key technologies employed include: complete device self-testing, hardware calibration, and pre-loading of process models. This is done to ensure the machine can operate stably in space.

[0121] Furthermore, the specific process of step 2 is as follows:

[0122] 1) The microcontroller drives the pump set to synchronously push organic phase and aqueous phase precursor liquid. The fluid enters the hairpin-shaped steady flow input pipe, and the flow pulsation is eliminated by the bending flow channel, so that the pressure and flow rate of the two fluids are kept consistent.

[0123] 2) The two fluids converge into the semi-circular upper chamber along the symmetrical inlet of the chip, forming a 180° concentric high-speed impact jet. The turbulence is generated by the fluid kinetic energy, breaking the traditional laminar molecular diffusion limitation.

[0124] 3) The sensing hardware collects the jet velocity Vjet and impact Reynolds number Re in real time. The microcontroller uses the microgravity correction mixing time formula to calculate the theoretical mixing time tmix in real time and automatically adjusts the precursor liquid flow rate in a closed loop.

[0125] 4) The counter-turbulent fluid flows downward into the conical lower chamber, completing the first stage of active impact mixing, and then enters the passive enhanced mixing channel.

[0126] Supplementary Note 7

[0127] The purpose of step 2 above is to rapidly mix the raw materials using a "water jet" method (primary mixing); addressing the problem that existing technologies are slow and rely on molecular diffusion. This application transforms the two pharmaceutical solutions (precursor solutions) into two high-speed water jets, causing them to collide violently within the chip. The "impact force" and "turbulence" generated by this impact instantly and evenly mix the two solutions, much faster than slow stirring. The key technology employed is a 180° coaxial opposing jet mixing time formula (microgravity correction). This formula automatically adjusts the "water jet's" force (flow rate) based on the specific conditions of space (such as microgravity), ensuring precise mixing time.

[0128] Furthermore, the specific process of step 3 is as follows:

[0129] 1) The mixed fluid flows through the 40μm×40μm staggered herringbone channels that are repeatedly arranged along the central axis S in the conical lower cavity; the fluid continues to stratify, shear, and fold, further reducing the solute diffusion distance, and the system instantly reaches a highly supersaturated state.

[0130] 2) The microcontroller collects the real-time on-orbit temperature T, microgravity supersaturation offset ΔSspace, and ground reference supersaturation Sr, substitutes them into the space supersaturation correction nucleation rate formula to calculate the real-time nucleation rate B, and dynamically corrects the jet intensity.

[0131] 3) Under the synergistic effect of two-stage mixing, the solute bursts and nucleates simultaneously throughout the entire flow channel, controlling the uniformity of nanoparticles from the source of the process and ensuring that the product PDI < 0.15 in the high-throughput range.

[0132] Supplementary Note 8

[0133] The purpose of step 3 above is to further process the raw materials using a "V-shaped maze" to ensure sufficient reaction (secondary mixing and nucleation). This addresses the issue that after impact mixing, some areas may not be fully mixed, and drug particles need to begin forming (nucleation). This application guides the mixed liquid into a special "V-shaped" channel, where it is continuously divided into smaller streams, compressed, and folded, much like navigating a maze. This allows for more thorough contact of the raw materials, and in the microgravity environment of space, a "space-corrected nucleation rate formula" precisely controls the initial formation speed and size of the drug particles, resulting in more uniform growth. Key technologies employed include: staggered V-shaped channels and a space-corrected nucleation rate formula. This essentially "insures" the "birth" process of the drug particles, ensuring they all begin forming at roughly the same time and under similar conditions.

[0134] Furthermore, the specific process of step 4 is as follows:

[0135] 1) After nucleation, the mixed fluid flows into the serpentine constant current output tube with an aspect ratio > 10:1. The long flow channel provides sufficient residence time, and the small crystal nuclei grow uniformly to the target particle size of 80~120nm. The COC chip in this solution is equipped with 2mm tempered glass, and the serpentine section is reserved with a dedicated coaxial optical detection window to adapt to the vertical transmission of the optical path.

[0136] 2) The integrated optical components are coaxially aligned with the detection window. The light source beam passes through the long-pass filter and the second set of functional filters in sequence to filter out short-wave scattering, spatial stray light, and solvent fluorescence interference, retaining only the characteristic scattering / transmission light signal of the nanoparticles. The signal receiving unit transmits a set of light intensity data back to the microcontroller every second.

[0137] 3) The microcontroller retrieves the pre-stored optical signal-particle size calibration curve and converts the light intensity into average particle size, dispersion index (PDI), and particle concentration in real time, forming a closed-loop control. This creates a fully automated closed-loop process of "counter-mixing - nucleation and growth - online optical detection - flow parameter self-correction." Ground-based devices only operate in an open-loop constant flow rate mode and lack real-time correction steps.

[0138] Supplementary Note 9

[0139] The purpose of step 4 above is to allow the drug particles to grow in a "long track" and to perform "real-time monitoring." The problem it solves is that after drug particles are formed, they need to grow to a suitable size, and their growth status needs to be monitored in real time; existing technologies cannot monitor this in real time. This application allows the particles to enter a long, winding channel (a serpentine channel), much like running a long-distance race, providing sufficient time for the particles to grow uniformly to the target size (e.g., 80-120 nanometers). Crucially, a "microscope" (optical detection component) in a "window" next to the channel can observe the particle size and uniformity in real time, transmitting this information to a computer. The computer then automatically adjusts the "water gun intensity" and the control of the "maze channel" based on this information, forming a "closed-loop" system that keeps the production process in optimal condition. Key technologies employed include: serpentine channel particle growth, integrated optical component in-situ real-time closed-loop monitoring, and particle size calibration curves. This is the "brain" of the entire process, capable of real-time feedback and adjustment to ensure the quality of the final product.

[0140] Furthermore, the specific process of step 5 is as follows:

[0141] 1) When the fluid flows to the midpoint of the buffer inlet at the end of the serpentine output tube, the microcontroller starts the third buffer pump and delivers the diluted buffer according to the preset ratio Q3=2×Q1.

[0142] 2) The buffer solution and the nanoparticle-containing stock solution are mixed uniformly online to rapidly reduce the concentration of organic solvent in the system, inhibit the aggregation and dissolution of nanoparticles, stabilize the dispersion system, and meet the requirements of long-term space storage.

[0143] 3) The optical components continuously collect the light signal of the diluted fluid. If the clustering characteristic scattering signal is detected, the microcontroller slightly increases the buffer flow rate to further reduce the solute concentration.

[0144] Supplementary Note 10

[0145] The purpose of step 5 above is to add a "diluent" to prevent drug particles from clumping together. The problem addressed is that drug nanoparticles are highly reactive and prone to clumping, affecting stability and efficacy. This application adds a "buffer solution" to dilute the drug particles before they reach a certain size and are ready for shipment. This is like adding a "sedative" to an active child, reducing their activity, preventing clumping, and allowing them to remain stable for later storage and use in space. If signs of clumping are detected, the amount of diluent will be automatically increased. The key technology used is online mid-point dilution with the buffer solution. This is equivalent to adding a "stabilizer" to the final product.

[0146] Furthermore, the specific process of step 6 is as follows:

[0147] 1) The diluted and stabilized nanodrug suspension is introduced into an aerospace-grade sealed pressure sample cell to complete the collection of the synthesized product in orbit. The sample cell can be directly used for astronaut drug delivery and long-term sealed storage.

[0148] 2) The entire synthesis process is continuously timed t. The microcontroller reads the precursor liquid concentration C0, two-channel flow rate, and measured raw material utilization rate η in real time. It continuously inputs the data into the high-throughput production calculation formula to dynamically calculate the cumulative total synthesis output Y. The output data is automatically stored in orbit and supports remote reading of output information from the ground.

[0149] 3) Automatic determination of synthesis endpoint: When the cumulative output Y reaches the preset target value, or the synthesis time reaches the set threshold, the microcontroller automatically shuts down the three flow pumps, and the optical components maintain a low-power standby monitoring state.

[0150] Supplementary Note 11

[0151] Step 6 above serves the purpose of secure packaging and production statistics. It addresses the need to collect the drug and determine the total production volume. The diluted and stabilized drug solution is directly collected into a sealed, space-specific container (sample pool), which can be used directly by astronauts or stored long-term. Simultaneously, the system records the entire process time and raw material usage, using a production formula to calculate the total drug production volume in real time, and transmits the data back to Earth. Key technologies employed include: on-orbit sealed collection of the product and a high-throughput production formula. This achieves the function of "made-to-use, real-time statistics."

[0152] Furthermore, the specific process of step 7 is as follows:

[0153] 1) Switch the rinsing buffer pathway. Use high-flow PBS buffer to rinse the steady-flow input channel, pear-shaped mixing chamber, herringbone mixing channel, serpentine optical detection channel, and dilution tubing in sequence to remove residual drug nanoparticles from the tube walls and prevent long-term adsorption and blockage of the flow channels. The low adsorption properties of COC material greatly shorten the cleaning time.

[0154] 2) After rinsing, blank buffer solution is introduced again, and the optical components re-acquire the baseline light signal to eliminate the interference of trace residual impurities on the tube wall on the next round of detection.

[0155] 3) Turn off the light source, flow pump, and sensor module. The device enters a low-power on-orbit standby mode and waits for the next synthesis command.

[0156] Supplementary Note 12

[0157] The purpose of step 7 above is to clean and prepare the equipment for the next operation. It addresses the issue that the equipment needs to be thoroughly cleaned after each production run before the next task. After production, the system automatically flushes all pipes with a liquid called a "buffer solution" to remove any residual drug particles and prevent blockages. Then, a simple optical inspection is performed again to ensure the channels are clean. Finally, all equipment enters a low-power standby mode, awaiting the next instruction. Key technologies employed include automatic flow channel cleaning and secondary optical path calibration, ensuring the equipment's reusability and lifespan.

[0158] In summary, the above seven steps resemble a sophisticated "space pharmaceutical factory assembly line":

[0159] Step 1: Conduct a thorough pre-start check to ensure everything is in order.

[0160] The second and third steps involve using a powerful "water gun" and a "V-shaped maze" to quickly and evenly mix the raw materials and control the "birth" of drug particles.

[0161] Step 4: Allow the particles to grow to the appropriate size in the "long track" and continuously adjust the production process through "real-time checks" to ensure quality.

[0162] Step 5: Add a "stabilizer" to prevent the drug particles from clumping together.

[0163] Step 6: Safely "pack" the prepared medicine and know the yield.

[0164] Step 7: Clean up thoroughly to prepare for the next production run.

[0165] These steps solve a series of problems in existing technologies, such as slow and uneven mixing, unsuitable materials, difficult operation, and inability to control in real time in the space environment, and enable efficient, stable, and high-yield preparation of drug nanoparticles in the extreme environment of space. Example 1

[0166] 1. Chip fabrication

[0167] COC sheet metal is vacuum hot-pressed, with a channel accuracy of ±1μm; vacuum key with 2mm tempered glass plate.

[0168] It is suitable for vacuum resistance, pressure differential resistance, and leak-free operation.

[0169] 2. Flow control parameters

[0170] Microcontroller-driven flow pump: Q1=Q2=10ml / min; Q3=20ml / min; flow accuracy ±1μl / min.

[0171] Examples of space drug synthesis:

[0172] Taking PEG-PLGA drug nanoparticles as an example: the organic phase is acetonitrile, the solute is PEG-PLGA 5–20 mg / ml; the aqueous phase is PBS buffer; the synthesized particle size is ~100 nm; the PDI is ~0.12; the raw material utilization rate is 92%, which meets the requirements for space drug delivery.

[0173] 4. On-orbit adaptive calibration: Using the space control formula as a model, parameter drift caused by microgravity is compensated in real time to ensure the stability and repeatability of the synthesis.

[0174] The above description is merely a preferred embodiment of the present invention and is not intended to limit the invention. Any modifications, equivalent substitutions, and improvements made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A high-throughput impingement jet synthesis method for space drug synthesis, characterized in that, This method is based on a space-based high-throughput impingement jet synthesis device. The core of this device is an aerospace-grade COC microfluidic chip, along with fluid delivery pipelines, a fluid inlet interface, a sealed sample collection structure, and optical observation components. The COC microfluidic chip integrates a hairpin-type stabilizing input tube, a 180° coaxial counter-current mixing chamber, an interlaced herringbone-shaped secondary mixing channel, a serpentine particle growth channel with an optical detection window, a buffer midpoint dilution branch, and a full-channel cleaning pipeline. The method includes the following steps: Step 1: Preparation process: Power-on self-test of the entire machine in orbit, hardware calibration and pre-loading of the process model; Step 2: Primary active mixing stage: precursor liquid delivery, 180° coaxial counter-current jet generation, and dynamic flow rate control by calling the mixing time formula; Step 3: Synchronous nucleation stage: Primary active mixing stage: Secondary enhanced mixing through staggered herringbone channels, using the spatial nucleation rate formula to compensate for microgravity offset; Step 4: Serpentine channel particle growth + in-situ real-time closed-loop monitoring of integrated optical components; Step 5: Anti-agglomeration stabilization process: Online midpoint dilution of buffer solution to stabilize the nano-dispersion system; Step 6: Collection and Statistics Process: The product is collected in a sealed manner on track, and the output is dynamically calculated in real time using the production formula; Step 7: On-orbit reuse process: automatic cleaning of the flow channel, secondary calibration of the optical path, and finalization of the entire machine's standby operation.

2. The high-throughput impingement jet synthesis method for space drug synthesis according to claim 1, characterized in that: The specific process of step 1 is as follows: 1) When the spacecraft issues a start command, the entire synthesis device is powered on. The microcontroller synchronously drives the three-way flow pump, temperature / microgravity sensing module, and integrated optical detection component to start hardware self-test: verifying the airtightness of the COC microfluidic chip flow channel, the coaxiality of the optical path, the pump stroke accuracy, and the sensor signal path; if there is leakage, optical path obstruction, or pump control deviation, the process is automatically locked and the fault is reported. 2) Hardware zero-point calibration and flow base logic lock: The three flow pumps complete the zero-point calibration and lock the basic mixing logic: the flow rates of the two precursor liquids are Q1=Q2, and the flow rates of the buffer diluent are Q3=2Q1; The total volume of the buffer solution in the sealed sample cell is set to be 10 times the volume of the organic phase. 3) Loading Space Quantization Control Formulas: The microcontroller reads real-time on-orbit environmental parameters (chamber temperature T, microgravity supersaturation offset ΔSspace, hybrid cavity feature size Dch, cavity morphology coefficient k), and pre-stores three sets of staged control formulas as the benchmark for the entire process: 4) Raw material loading and flow channel pre-wetting: Connect the drug-loaded organic phase, aqueous antisolvent, and PBS buffer diluent to the three-way syringe respectively; the low-speed delivery fluid flows sequentially through the hairpin-shaped steady flow input tube, the pear-shaped mixing chamber, the staggered herringbone channel, and the serpentine optical detection flow channel to empty the air bubbles that are easy to accumulate under microgravity environment and eliminate jet pulsation and optical detection interference.

3. The high-throughput impingement jet synthesis method for space drug synthesis according to claim 1, characterized in that: The specific steps of process 4) in step 1 are as follows: ① Formula for mixing time of impingement jet (used during the counter-mixing stage): ; Among them, t mix Mixing time (ms); k: cavity morphology coefficient; D ch : Characteristic dimensions of the mixing chamber (μm); V jet : Impact jet velocity (m / s); Re: Impact Reynolds number; ② Formula for the nucleation rate of nanoparticles (with spatial supersaturation correction); ; Where B: nucleation rate; k1: nucleation rate frequency factor; γ: surface tension; v m : Molar volume; kB: Boltzmann constant; T: Absolute temperature; Sᵣ: Ground supersaturation; ΔSspace: Space microgravity supersaturation offset; ③ High-throughput production formula: ； Where Y: total yield (mg); C o : Precursor concentration (mg / ml); η: Raw material utilization rate (>90%); t: Synthesis time (min); Q1 and Q2 are the flow rates of the two precursor solutions, respectively.

4. The high-throughput impingement jet synthesis method for space drug synthesis according to claim 1, characterized in that: The specific process of step 2 is as follows: 1) The microcontroller drives the pump set to synchronously push organic phase and aqueous phase precursor liquid. The fluid enters the hairpin-shaped steady flow input pipe, and the flow pulsation is eliminated by the bending flow channel. The pressure and flow rate of the two fluids are kept consistent. 2) The two fluids converge into the semi-circular upper chamber along the symmetrical inlet of the chip, forming a 180° concentric high-speed impact jet. The turbulence is generated by the fluid kinetic energy, which breaks the traditional laminar molecular diffusion limitation. 3) The sensing hardware collects the jet velocity Vjet and impact Reynolds number Re in real time. The microcontroller uses the microgravity correction mixing time formula to calculate the theoretical mixing time tmix in real time and automatically adjusts the precursor liquid flow rate in a closed loop. 4) The counter-turbulent fluid flows downward into the conical lower chamber, completing the first stage of active impact mixing, and then enters the passive enhanced mixing channel.

5. The high-throughput impingement jet synthesis method for space drug synthesis according to claim 1, characterized in that: The specific process of step 3 is as follows: 1) The mixed fluid flows through the 40μm×40μm staggered herringbone channels that are repeatedly arranged along the central axis S in the conical lower cavity; the fluid continuously stratifies, shears, and folds, further reducing the solute diffusion distance, and the system instantaneously reaches a highly supersaturated state; 2) The microcontroller collects the real-time on-orbit temperature T, microgravity supersaturation offset ΔSspace, and ground reference supersaturation Sr, substitutes them into the space supersaturation correction nucleation rate formula to calculate the real-time nucleation rate B, and dynamically corrects the jet intensity. 3) Under the synergistic effect of two-stage mixing, the solute bursts and nucleates simultaneously throughout the entire flow channel, controlling the uniformity of nanoparticles from the source of the process and ensuring that the product PDI < 0.15 in the high-throughput range.

6. The high-throughput impingement jet synthesis method for space drug synthesis according to claim 1, characterized in that: The specific process of step 4 is as follows: 1) After nucleation, the mixed fluid flows into the serpentine constant current output tube with an aspect ratio > 10:

1. The long flow channel provides sufficient residence time, and the fine crystal nuclei grow uniformly to the target particle size of 80~120nm. The COC chip in this solution is equipped with 2mm tempered glass, and the serpentine section has a reserved dedicated coaxial optical detection window to adapt to the vertical transmission of the optical path. 2) The integrated optical components are coaxially aligned with the detection window. The light source beam passes through the long-pass filter and the second set of functional filters in sequence to filter out short-wave scattering, spatial stray light, and solvent fluorescence interference, retaining only the characteristic scattering / transmission light signal of the nanoparticles; the signal receiving unit transmits one set of light intensity data back to the microcontroller every second. 3) The microcontroller retrieves the pre-stored optical signal-particle size calibration curve and converts the light intensity into average particle size, dispersion degree (PDI), and particle concentration in real time to form a closed-loop control; forming a fully automatic closed-loop process of "counter-mixing-nucleation growth-online optical detection-flow parameter self-correction". The ground-based device only operates in open loop at a constant flow rate and has no real-time correction step.

7. The high-throughput impingement jet synthesis method for space drug synthesis according to claim 1, characterized in that: The specific process of step 5 is as follows: 1) When the fluid flows to the midpoint of the buffer inlet at the end of the serpentine output tube, the microcontroller starts the third buffer pump and delivers the diluted buffer according to the preset ratio Q3=2×Q1; 2) The buffer solution and the nanoparticle-containing stock solution are mixed uniformly online to rapidly reduce the concentration of organic solvent in the system, inhibit the aggregation and dissolution of nanoparticles, stabilize the dispersion system, and meet the requirements for long-term space storage. 3) The optical components continuously collect the light signal of the diluted fluid. If the clustering characteristic scattering signal is detected, the microcontroller slightly increases the buffer flow rate to further reduce the solute concentration.

8. The high-throughput impingement jet synthesis method for space drug synthesis according to claim 1, characterized in that: The specific process of step 6 is as follows: 1) The diluted and stabilized nanodrug suspension is introduced into an aerospace-grade sealed pressure sample cell to complete the collection of the synthesized product in orbit. The sample cell can be directly used for astronaut drug delivery and long-term sealed storage. 2) The entire synthesis process is continuously timed t. The microcontroller reads the precursor liquid concentration C0, two-channel flow rate, and measured raw material utilization rate η in real time. It continuously substitutes these values ​​into the high-throughput production calculation formula to dynamically calculate the cumulative total synthesis output Y. The output data is automatically stored in orbit and supports remote reading of output information from the ground. 3) Automatic determination of synthesis endpoint: When the cumulative output Y reaches the preset target value, or the synthesis time reaches the set threshold, the microcontroller automatically shuts down the three flow pumps, and the optical components maintain a low-power standby monitoring state.

9. The high-throughput impingement jet synthesis method for space drug synthesis according to claim 1, characterized in that: The specific process of step 7 is as follows: 1) Switch the rinsing buffer pathway. Use high-flow-rate PBS buffer to sequentially rinse the constant flow input channel, pear-shaped mixing chamber, herringbone mixing channel, serpentine optical detection channel, and dilution tubing to remove residual drug nanoparticles from the tubing walls and prevent long-term adsorption and blockage of the flow channels. The low adsorption properties of COC material significantly shorten the rinsing time. 2) After rinsing, blank buffer solution is introduced again, and the optical components re-acquire the baseline light signal to eliminate the interference of trace residual impurities on the tube wall on the next round of detection; 3) Turn off the light source, flow pump, and sensor module. The device enters a low-power on-orbit standby mode and waits for the next synthesis command.

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